Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the influence of beta-adrenergic receptor activation on the control of gap junctional conductance (gj) in the heart of cardiomyopathic hamsters (11 months old). We measured gj in isolated ventricular cell pairs using two voltage-clamp circuits. Administration of isoproterenol (10(-6) mol/L) to the bath had no effect on gj in myopathic cell pairs but increased gj by 45 +/- 3% (+/- SE) in normal hamsters. Moreover, forskolin (10(-7) mol/L), an activator of adenyl cyclase, did not change gj in myopathic cells but enhanced gj by 23 +/- 2.8% in controls. Similar results were obtained with isobutylmethylxanthine (10(-6) mol/L), a phosphodiesterase inhibitor. Dibutyryl-cAMP (10(-6) mol/L), however, increased gj of cardiomyopathic cell pairs by 58 +/- 2.1% within 2 minutes and enhanced gj in controls by 50 +/- 3.6%. The effect of dibutyryl-cAMP on gj of myopathic cells was suppressed by intracellular dialysis of an inhibitor of protein kinase A. These observations indicate that the regulation of gj by the beta-adrenergic receptor-G protein-adenyl cyclase signaling system is greatly impaired in the failing heart but the ability of cAMP to increase gj is still preserved.
Hypertension 1996 Feb
PMID:Impaired regulation of cell communication by beta-adrenergic receptor activation in the failing heart. 856 50

Nitric oxide inhibits proliferation and migration of vascular smooth muscle cells and contractility of cardiomyocytes in vitro. In spontaneously hypertensive rats (SHR), evidence suggests intrinsic abnormalities of the L-arginine-nitric oxide axis, such as low cGMP-dependent protein kinase in the heart and abnormal L-arginine metabolism. To investigate the in vivo effect of L-arginine on cardiac hypertrophy, 30 SHR and 30 Wistar-Kyoto rats (WKY) were randomly grouped to receive L-arginine (7.5 g/L in drinking water) or vehicle for 12 weeks. L-Arginine treatment did not affect body weight or arterial pressure in either strain. In vehicle-treated animals, the heart/body weight ratio was significantly higher in SHR than in WKY (P < .01). L-Arginine treatment decreased the heart/body weight ratio in SHR (P < .05) but did not affect it in WKY. Expression of skeletal alpha-actin mRNA, known to be expressed in the hypertrophied myocardium, was attenuated in L-arginine-treated SHR compared with vehicle-treated SHR. Cardiac cGMP content and nitrate/nitrite content were less in SHR than WKY. L-Arginine treatment increased these levels only in SHR, suggesting enhanced nitric oxide production. Thus, chronic L-arginine administration attenuated cardiac hypertrophy independently of blood pressure and increased myocardial content of cGMP and nitrate/nitrite. Our results suggest that abnormality of the cardiac L-arginine-nitric oxide axis may play an important role in the pathogenesis of cardiac hypertrophy in SHR.
Hypertension 1996 Jan
PMID:Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. 859 77

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
Hypertension 1996 Mar
PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone-stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone-stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone-stimulated water permeability was 317 +/- 47 microm/s (P < .001). Addition of spermine NONOate, a nitric oxide donor, to the bath decreased water permeability to 74 +/- 38 microm/s (P < .002). In the presence of LY 83583, an inhibitor of soluble guanylate cyclase, spermine NONOate did not change water permeability. Addition of spermine NONOate increased cGMP production (P < .01). In the presence of the cGMP-dependent protein kinase inhibitor, spermine NONOate did not change water permeability. Since antidiuretic hormone increases water permeability by increasing cAMP, we hypothesized that nitric oxide inhibits water permeability by decreasing cAMP. In tubules pretreated with antidiuretic hormone, intracellular cAMP was 18.9 +/- 3.9 fmol/mm. In tubules treated with antidiuretic hormone and spermine NONOate, cAMP was 9.3 +/- 1.7 fmol/mm (P < .03). We also examined the effect of spermine NONOate on dibutyryl-cAMP-stimulated water permeability. In the presence of dibutyryl-cAMP, water permeability was 388 +/- 30 microm/s. Addition of spermine NONOate had no significant effect on water permeability. Time controls and inhibitors by themselves did not change antidiuretic hormone-stimulated water permeability. We concluded that nitric oxide decreases antidiuretic hormone-stimulated water permeability by increasing cGMP via soluble guanylate cyclase, activating cGMP-dependent protein kinase and decreasing cAMP.
Hypertension 1996 Mar
PMID:Mechanism of the nitric oxide-induced blockade of collecting duct water permeability. 861 24

This study examines the role of the cAMP signaling pathway in the regulation of 45Ca influx in cultured vascular smooth muscle cells from the rat aorta. K+o-induced depolarization of smooth muscle cells increased the rate of 45Ca uptake by twofold to threefold. This effect was completely abolished by the dihydropyridine derivatives nifedipine and nicardipine, with a Ki of 3 and 10 nmol/L, respectively. Activators of cAMP signaling (isoproterenol, forskolin, cholera toxin) increased cAMP content by 50- to 100-fold and decreased voltage-dependent 45Ca uptake by 50% to 70%. Neither the dihydropyridines nor the cAMP activators affected basal 45Ca influx. Direct addition of the protein kinase inhibitor H-89 to the incubation medium in the 1- to 10-micromol/L range did not alter basal 45Ca uptake but completely abolished voltage-dependent Ca2+ transport. Preincubation of cells for 1 hour with 10 micromol/L H-89 did not modify basal and depolarization-induced 45Ca uptake in H-89-free medium but prevented forskolin-induced inhibition of voltage-dependent Ca2+ influx. The addition of cytoskeleton-active compounds reduced voltage-dependent Ca2+ transport and completely abolished its regulation by cAMP. Activation of cAMP signaling decreased the volume of smooth muscle cells by 12% to 15%. The same cell volume diminution in hyperosmotic medium did not alter voltage-dependent 45Ca uptake. Thus, data obtained in this study show that in contrast to cardiac and skeletal myocytes, in vascular smooth muscle cells, 45Ca influx, putatively due to L-type channels, is inhibited by cAMP. This regulatory pathway appears to be mediated via protein kinase A activation and cytoskeleton reorganization.
Hypertension 1996 Mar
PMID:cAMP signaling inhibits dihydropyridine-sensitive Ca2+ influx in vascular smooth muscle cells. 861 39

cGMP-based regulatory systems are vital for counteracting the renin-angiotensin system (RAS) which promotes volume expansion and high blood pressure. Natriuretic peptides and nitric oxide acting through their second messenger cGMP normally increase natriuresis and diuresis, and regulate renin release; however, the severe pathological state of cardiac heart failure is characterized by elevated levels of atrial natriuretic peptide that are no longer able to effectively oppose exaggerated RAS effects. There is presently limited information on the intracellular effectors of cGMP actions in the kidney. Recently we reported the cloning of the cDNA for type II cGMP-dependent protein kinase (cGK II), which is highly enriched in intestinal mucosa but was also detected for the first time in kidney. In the present study, cGK II was localized to juxtaglomerular (JG) cells, the ascending thin limb (ATL), and to a lesser extent the brush border of proximal tubules. An activator of renin gene expression, the angiotensin II type I receptor inhibitor, losartan, increased cGK II mRNA and protein three to fourfold in JG cells. In other experiments, water deprivation increased cGK II mRNA and protein three to fourfold in the inner medulla where both cGK II, and a kidney specific CI- channel shown by others to be regulated by dehydration, are localized in the ATL. Whereas additional data suggest that cGK I may primarily mediate cGMP-related changes in renal hemodynamics, cGK II may regulate renin release and ATL ion transport.
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PMID:Expression of type II cGMP-dependent protein kinase in rat kidney is regulated by dehydration and correlated with renin gene expression. 869 57

The role of cyclic AMP-dependent protein kinase (PKA) and systolic function during the development of left ventricular hypertrophy (LVH) still remain uncertain. The aim of this work is to study PkA activity and mechanical heart function in two experimental heart hypertrophy models: specifically, one induced by pressure overload (Goldblatt model: two kidneys, one clamped, Gb); and another secondary to myocardial infarction (MI) generated by ligation of the left coronary artery. Hypertension in the Gb group becomes evident by the third and fourth week after surgery without any significant change in the corresponding sham group. The myocardial infarction group did not show any change in systolic pressure. Different degrees of LVH for the two experimental models were observed. Relative cardiac mass (RCM) and relative ventricular mass (RVM) increased 23 and 16%, respectively, above the sham-operated rats in MI group (P < 0.05). For the pressure overload model, the increase values were 42 and 44%, respectively (P < 0.05). Left ventricular hypertrophy was also evaluated through quantitative changes in cardiac beta-myosin heavy chain which agreed with morphometric studies in Goldblatt rats. Ventricular PKA activity did not show any significant difference with respect to the sham-operated group after induction of pressure overload. For the MI model, ventricular PKA activity changed only at day 7 post-infarction with a 289% increase above the sham-operated group (P < 0.05). The absence of activation of ventricular PKA after constriction of renal artery or myocardial infarction was also corroborated by the patterns of PKA-dependent phosphorylated proteins. While force-generating capacity was increased, there was no change in ventricular PKA activity, indicating that there is no relation between this enzyme and systolic stress-strain regression lines in either pressure overload or myocardial infarction conditions. Cyclic AMP-dependent protein kinase activity had no relation with development of cardiac hypertrophy in the two experimental models of LVH. These findings contribute to the hypothesis for a multifactorial interaction of different intracellular biochemical and molecular mechanisms in the genesis of cardiac hypertrophy.
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PMID:Cyclic AMP-dependent protein kinase and mechanical heart function in ventricular hypertrophy induced by pressure overload or secondary to myocardial infarction. 876 44

Hypertension is a multifactorial disorder that results in an increased risk of cardiovascular and end-stage renal disease. Liddle's disease represents a specific hypertensive disease and expresses itself in the human population as an autosomal dominant trait. Recent experimental evidence indicates that patients with Liddle's disease have constitutively active amiloride-sensitive Na+ channels and that these channels are phenotypically expressed in lymphocytes obtained from normal and affected members of the original Liddle's kindred. Linkage analysis indicates that this disease results from a deletion of the carboxy-terminal region of the beta-subunit of a recently cloned epithelial Na+ channel (ENaC). We report the successful immunopurification and reconstitution of both normal and constitutively active lymphocyte Na+ channels into planar lipid bilayers. These channels display all of the characteristics typical of renal Na+ channels, including sensitivity to protein kinase A phosphorylation. We demonstrate that gating of normal Na+ channels is removed by cytoplasmic trypsin digestion and that the constitutively active Liddle's Na+ channels are blocked by a beta- or gamma-ENaC carboxy-terminal peptide in a GTP-dependent fashion.
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PMID:Peptide block of constitutively activated Na+ channels in Liddle's disease. 877 47

We tested the hypothesis as to whether elevated arterial pressure in hypertension alters cGMP, or cAMP, mediated vasorelaxation. Relaxation to nitroglycerin and isoproterenol was determined in isolated aortic rings from one-kidney, one clip hypertensive (1K1C), coarctation hypertensive (CH) and normotensive control (C) rats. Thoracic aortas from 1K1C and CH rats, as well as abdominal aortas from 1K1C rats, but not abdominal aortas from CH rats were exposed chronically (4-6 weeks) to elevated arterial pressure. Sensitivity of rings with and without endothelium to nitroglycerin was suppressed significantly only in vessels exposed chronically to high arterial pressure. Impaired sensitivity to nitroglycerin in abdominal rings from 1K1C rats could not be abolished by exposure to 100 uM L-arginine, the substrate for production of NO by endothelial nitric oxide synthase, or 100 uM L-cysteine, the source of thiol groups required for the production of nitric oxide from nitroglycerin. Maximum relaxation to isoproterenol was impaired significantly in thoracic and abdominal rings, with and without endothelium, from 1K1C and CH rats. Relaxation to 8-bromo-cGMP and dibutyryl cAMP was similar in abdominal rings from all groups. We conclude that impaired vasorelaxation to nitroglycerin and isoproterenol in hypertension involves mechanisms prior to activation of vascular smooth muscle cGMP-dependent and cAMP-dependent protein kinase, respectively. Impaired cGMP, but not cAMP, mediated relaxation of aortas appears to result from their exposure to high arterial pressure per se. This effect does not appear to involve the vascular endothelium or vascular sources of thiols, but rather may reflect an effect of high arterial pressure to impair the ability of the artery to respond to nitric oxide derived from nitroglycerin.
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PMID:Selective effect of high arterial pressure in hypertension upon inhibition of cGMP versus cAMP mediated vascular relaxation. 884 63

In order to elucidate the signal transduction pathway from external mechanical stress to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK) and MAP kinases (MAPKs) in neonatal rat cardiac myocytes. Mechanical stretch transiently activated Raf-1 and MAPKK with a peak at 2 and 5 min after stretch, respectively. In addition, MAPKs were maximally activated at 8 min after stretch. Next, the relationship between stretch-induced hypertrophy and the cardiac reninangiotensin system was investigated. When the stretch-conditioned culture medium was transferred to non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type I angiotensin II (AngII) receptor antagonist, CV-11974. Moreover, in in vivo studies using spontaneously hypertensive rats, hypertension-induced cardiac hypertrophy was significantly reduced by treatment with subpressure doses of CV-11974. In addition, CV-11974 reduced the isozymic transition of MHC from VI to V3 and inhibited the accumulation of collagen fibers in the extracellular space of the myocardium. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK and MAPKs. AngII, which is secreted from stretched myocytes, possibly activates these protein kinases. Moreover, it was shown that CV-11974 causes regression of cardiac hypertrophy and has cardioprotective effects on hypertrophied myocardium in vivo.
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PMID:Angiotensin II mediates mechanical stress-induced cardiac hypertrophy. 896 84


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